This is a proposal to establish a Head Injury Research Center at the University of Vermont for the purposes of elucidating the role of the cerebrovascular endothelium in the development of secondary brain injury due to ischemia and intracranial hypertension. The investigators will test the hypothesis that derangements in cerebrovascular endothelium after brain injury, with or without shock and resuscitation, lead to perturbations in cerebral blood flow, thrombosis, and neutrophil activation/accumulation which promote vasogenic edema, brain swelling and increased intracranial pressure. The specific aims encompass five interrelated areas of inquiry. PROJECT I will examine the role of the cerebrovascular endothelium in the control of pial anterior tone after brain injury alone, brain injury combined with hemorrhagic shock, and shock alone in a porcine model. PROJECT II will examine the effect of a percussion insult on endothelial regulation of thrombosis and fibrinolysis in an ex vivo model using segments of human pial arteries. PROJECT III will construct a mathematical model of intracranial pressure dynamics based upon changes in the vascular, cerebrospinal fluid, and brain tissue compartments in the normal and injured brain using a rabbit model for validation. PROJECT IV will examine the effect of neutrophil/endothelial interactions in the production of vasogenic edema in a rabbit model brain injury. PROJECT V will examine the effect of the osmolarity of intravenous fluids used for resuscitation on intracranial pressure in patients with moderate and severe brain injuries. The results of these studies should provide insights into the pathogenesis of ischemic secondary brain injury and provide direction for future therapy.